Process for preparing optically active mevalonolactone compounds

ABSTRACT

The process for preparing mevalonolactone compounds is carried out by means of batch system chromatography or a simulated moving bed chromatographic process using columns filled with an optical resolution filler comprising a polysaccharide derivative. The simulated moving bed chromatographic process comprises forming a circulation flow circuit comprising a plurality of columns endlessly connected in series; enforcing a fluid to flow through the circuit in one direction; providing the column series alternately with an inlet port through which the fluid is introduced into the column in the flow direction and with an outlet port, through which the fluid is taken out; intermittently shifting activation of the inlet port and the outlet port in the direction of the fluid flow; introducing a solution containing a racemic mevalonolactone compound and an eluent through an inlet port into the circuit; and simultaneously taking out a solution rich in the weakly adsorbable substance and a solution rich in the strongly adsorbable and desorbed substance through the outlet port.

TECHNICAL FIELD THE INVENTION

This invention relates to a process for preparing optically activemevalonolactone compounds. More particularly, this invention relates toa commercial process for preparing optically active mevalonolactonecompounds which are useful for prevention and treatment of hyperlipemia,arteriosclerosis, etc.

BACKGROUND OF THE INVENTION

With respect to pharmaceutical compounds which have an asymmetriccenter, it is known that optical isomers of some of such compoundsrespectively have different physiological activities. That is, oftenonly one of the isomers has physiological effect in vivo or only one ofthem has terato-geneticity as seen in thalidomide. However, it isdifficult to optically separate a racemic compound by a conventionalmethod such as distillation, crystallization, etc. Thus most of thepharmaceutical compounds having an asymmetric center are marketed in theform of a racemic compound.

Under the circumstances, a commercial process, by which only an opticalisomer of various such pharmaceutical compounds and intermediatecompounds therefor can be isolated, is strongly desired. Because, ifonly physiologically active and useful isomers can be used astherapeutics, a small dose suffices and abatement of undesirable sideeffect is expected.

Although physiologically active isomers of mevalonolactone compounds arevery useful for prevention and treatment of hyperlipemia,arteriosclerosis, etc., there has been no commercial process for opticalresolution.

The object of this invention is to solve the above-described problem. Inother words, the object of this invention is to isolate optically activeisomers of mevalonolactone compounds with high purity in a commercialscale.

DISCLOSURE OF THE INVENTION

In the present invention, batch system chromatography and simulatedmoving bed chromatographic process using columns filled with a fillerfor optical resolution are employed in order to solve theabove-described problem.

More particularly, the invention described in claim 1 is a process forpreparing an optically active mevalonolactone compound comprisingconducting optical resolution of the racemic mixture of an opticallyactive mevalonolactone compound by means of batch system chromatographywhich uses a column filled with a filler selected from a groupconsisting of particles of a polysaccharide ester derivative, particlesof a polysaccharide carbamate derivative and particles of a supportwhich carries a polysaccharide ester derivative and/or a polysaccharidecarbamate derivative.

The invention described in claim 2 is a process for preparing anoptically active mevalonolactone compound as described in claim 1,wherein the polysaccharide ester derivative and the polysaccharidecarbamate derivative are those in which part of or all of the hydrogenatoms on the hydroxy groups or amino groups of the polysaccharide aresubstituted with an atom groups represented by any of the followingchemical formulas (1) to (4): ##STR1## wherein R stands for an aromaticgroup which may contain a hetero atom and may be unsubstituted orsubstituted with at least one selected from a group consisting of analkyl group having 1-12 carbon atoms, an alkoxy group having 1-12 carbonatoms, an alkylthio group having 1-12 carbon atoms, a cyano group, ahalogen atom, an acyl group having 1-8 carbon atoms, an acyloxy grouphaving 1-8 carbon atoms, a hydroxy group, an alkoxycarbonyl group having1-12 carbon atoms, a nitro group, an amino group and an alkylamino grouphaving 1-8 carbon atoms; and X stands for a hydrocarbon group having 1-4carbon atoms, which may contain a double bond or triple bond.

The invention described in claim 3 is a process for preparing anoptically active mevalonolactone compound comprising forming acirculation flow circuit comprising a plurality of columns filled withan optical resolution filler and endlessly connected in series;enforcing a fluid to flow through the circuit in one direction;providing each with an inlet port through which the fluid is introducedinto the column in the flow direction and with an outlet port, throughwhich the fluid is taken out; intermittently shifting the workingposition of the inlet port and a suitably-spaced outlet port in thedirection of the fluid flow; introducing a solution containing a racemicmevalonolacton compound and an eluent through an inlet port into thecircuit; and simultaneously taking out a solution rich in the weaklyadsorbable and a solution rich in the strongly adsorbable through theoutlet port.

The invention described in claim 4 is a process for preparing anoptically active mevalonolactone compound as described in claim 3,wherein the optical resolution filler is one selected from a groupconsisting of particles of a polysaccharide ester derivative, particlesof a polysaccharide carbamate derivative and particles of a supportwhich carries a polysaccharide ester derivative and/or a polysaccharidecarbamate derivative.

The invention described in claim 5 is a process for preparing anoptically active mevalonolacton compound as described in claim 4,wherein the polysaccharide ester derivative and the polysaccharide arethose in which part of or all of the hydrogen atoms on the hydroxygroups or amino groups of the polysaccharide are substituted with any ofthe atom groups represented by the following chemical formulas (1) to(4): ##STR2## wherein R stands for an aromatic group which may contain ahetero atom and may be unsubstituted or substituted with at least oneselected from a group consisting of an alkyl group having 1-12 carbonatoms, an alkoxy group having 1-12 carbon atoms, an alkylthio grouphaving 1-12 carbon atoms, a cyano group, a halogen atom, an acyl grouphaving 1-8 carbon atoms, an acyloxy group having 1-8 carbon atoms, ahydroxy group, an alkoxycarbonyl group having 1-12 carbon atoms, a nitrogroup, an amino group and an alkylamino group having 1-8 carbon atoms;and X stands for a hydrocarbon group having 1-4 carbon atoms, which maycontain a double bond or triple bond.

The invention described in claim 6 is a process for preparing anoptically active mevalonolactone compound as described in any of claims1 to 5, wherein the optically active mevalonolactone compound is ethyl7-2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl!-5-hydroxy-3-oxo-6-heptenoateor ethyl 7-2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl!-3,5-dihydroxy-6-heptenoate.

Mevalonolactone compounds handled in the process of the presentinvention are represented by a chemical formula (5) ##STR3## wherein Ris a carbocyclic aromatic group, heterocyclic aromatic group or fusedring heterocyclic aromatic groups having a sp² carbon atom; and Z is agroup represented by a chemical formula (6): ##STR4## wherein A standsfor ##STR5## R¹ is a hydrogen atom, a straight chain or branched C₁₋₄alkyl, phenyl or aralkyl; or Z is a group represented by a chemicalformula (7): ##STR6##

Specific examples of the mevalonolactone compounds represented bychemical formula (5) are ethyl 7-2-cyclopropyl-4(4-fluorophenyl)quinolin-3-yl!-5-hydroxy-3-oxo-6-heptenoaterepresented by formula (8), ethyl 7-2-cyclopropyl-4(4-fluorophenyl)quinolin-3-yl!-3,5-hydroxy-6-heptenoaterepresented by formula (9) and 6-2-{2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl}ethenyl!-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-onrepresented by formula (10) ##STR7##

Now we will discuss the optical resolution fillers used in the presentinvention.

Various resolution fillers can be used without any limitation if theyare able to optically separate a racemic mixture of optically activemevalonolactone compounds. Preferred optical resolution fillers usablein the present invention are selected from a group consisting ofparticles of a polysaccharide ester derivative, particles of apolysaccharide carbamate derivative and particles on which apolysaccharide ester derivative and/or a polysaccharide carbamatederivative is supported.

The polysaccharide of the above-mentioned polysaccharide esterderivative and polysaccharide carbamate derivative can be any ofnaturally occurring polysaccharide, modified natural polysaccharide,synthesized polysaccharide as well as oligo sugars. They can be usedwithout any limitation insofar as they are optically active.

Specific examples of the polysaccharides are: α-1,4-glucane (starch,glycogen, amylose), β-1,4-glucan (cellulose), α-1,6-glucan (dextran),β-1,3-glucan (curdlan, schizophylan), α-1,3-glucan, β-1,2-glucan (CrawnGall polysaccharide) α-1,6-mannan, β-1,4-mannan, β-1,2-fructan(inuline), β-2,6-fructan (levan), β-1,4-xylan, β-1,3-xylan,β-1,4-chitosan, β-1,4-N-acetylchitosan (chitin), α-1,3-1,6-glucan(mutan), pullulan, agalose, arginic acid, etc.

The number average polymerization degree (an average number of pyranoseor furanose rings) of these polysaccharides is up to 2,000. However, itis preferably not more than 500 in view of ease in handling.

As oligo sugars, maltose, maltotetraose, maltopentose, maltohexose,maltoheptose, isomaltose, eruose, paratinose, maltitol, maltotriisotol,maltotetraitol, isomaltitol, α-cyclodextrin, β-cyclodextrin,gamma-cyclodextrin, etc. can be referred to.

Examples of preferred polysaccharide ester derivatives andpolysaccharide carbamate derivative are polysaccharide compounds, ofwhich part of or all of the hydrogen atoms of the hydroxy or aminogroups is substituted with at least one of atom groups represented bythe chemical formulas (1), (2), (3) and (4): ##STR8## wherein R standsfor an aromatic group which may contain a hetero atom and may beunsubstituted or substituted with at least one selected from a groupconsisting of an alkyl group having 1-12 carbon atoms, an alkoxy grouphaving 1-12 carbon atoms, an alkylthio group having 1-12 carbon atoms, acyano group, a halogen atom, an acyl group having 1-8 carbon atoms, anacyloxy group having 1-8 carbon atoms, a hydroxy group, analkoxycarbonyl group having 1-12 carbon atoms, a nitro group, an aminogroup and an alkylamino group having 1-8 carbon atoms.

Examples of the aromatic groups are phenyl, naphthyl, phenanthryl,antracyl, indenyl, indanyl, furyl, thionyl, pyryl, benzofuryl,benzothionyl, indyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, etc. ofthese, phenyl, naphthyl, pyridyl, etc. are preferred.

X stands for a hydrocarbon group having 1-4 carbon atoms, which maycontain a double bond or triple bond. Examples of X are methylene,ethylene, ethylidene, ethenylene, ethynylene, 1,2- or 1,3-propylene,1,1- or 2,2-propylidine group, etc.

The degree of substitution with these atom groups is not less than 30%,preferably not less than 50% and more preferably not less than 80%.

The polysaccharides having the above substituents can be prepared byreacting an acid chloride or an isocyanate with the hydroxy or aminogroups of a polysaccharide.

In the process of this invention, particles of the above-mentionedpolysaccharide ester derivatives and/or polysaccharide carbamatederivatives can be used as optical resolution fillers. In this case, theparticle size of the polysaccharide ester derivatives and thepolysaccharide carbamate derivatives is usually 1 μm-1 mm, preferably 5μm-300 μm. The particles of polysaccharide ester derivatives andpolysaccharide carbamate derivatives may be poreless but it is preferredthat they are porous. The pore diameter of the porous particles is 10Å-100 μm, preferably 10 Å-5,000 Å.

In the process of the present invention, particles on which theabove-described polysaccharide ester derivatives and/or polysaccharidecarbamate derivatives are supported, can be used as an opticalresolution filler.

Organic and inorganic substances which can support the above-mentionedpolysaccharide ester derivatives or polysaccharide carbamate derivativescan be used as supports. Examples of the organic supports are particlesof polymers such as polystyrene, polyacrylamide, polyacrylate, etc.Examples of inorganic supports are silica gel, alumina, magnesia,zirconia, glass, kaolin, titanium oxide, silicate salts, diatomaceousearth, etc. The supports may be treated for modification of surfaceproperties.

These supports usually have a particle size of 1 μm-1 mm, preferably 5μm-300 μm. The particles may be poreless although it is preferred thatthey are porous. When they are porous, the pore size is 10 Å-100 μm,preferably 100 Å-5,000 Å. μm. The amount of the above-describedpolysaccharide ester derivatives and/or polysaccharide carbamatederivatives is usually 1-100 wt % of the amount of the support,preferably 5-50 wt %. With not more than 1 wt %, optical resolution of amevalonolactone may not be satisfactorily effected. If the amount is inexcess of 100 wt %, corresponding effect may not be expected.

In the process of this invention, as organic solvents, alcohols such asmethanol, ethanol, propanol, etc., hydrocarbons such as hexane as wellas a mixed solvent such as a mixture of a hydrocarbon and an alcohol,can be used as eluent for both batch system chromatography and simulatedmoving bed chromatographic process. A preferred eluent can be suitablyselected depending upon the species of the mevalonolactone compoundsubjected to optical resolution.

The batch system chromatography employed in the present invention isknown per se and commonly used.

The simulated moving bed chromatographic process comprises forming aflow circuit by endlessly connecting in series a plurality of columnsfilled with an optical resolution filler; enforcing a fluid to circulatethrough the circuit in one direction; providing the columns with aninlet port through which the fluid is introduced into the circuit in thedirection of the fluid flow and an outlet port through which the liquidis taken out; shifting the working positions of the inlet port and asuitably spaced outlet port intermittently in the direction of the fluidflow; introducing a solution containing a racemic compound which shouldbe optically separated and an eluent through an inlet port; andsimultaneously taking out a solution rich in the weakly adsorbedsubstances and a solution rich in the strongly adsorbed and desorbedsubstances through an outlet port.

In the simulated moving bed chromatographic process, a simulated movingbed, which comprises a plurality (12 or 8, for instance) of columnswhich are serially arranged in the circuit as shown in FIG. 1, is used.The fluid flows only in one direction. The number of the unit columns isnot limited to the numbers indicated above but it can be suitablyselected depending upon operation scale, consideration on chemicalengineering conditions, etc.

In this simulated moving bed, an inlet port for an eluent; an outletport through which a solution containing an optical isomer easilyadsorbable by the filler (extract) is taken out; an inlet port throughwhich a solution containing a racemic compound is introduced; and anoutlet port through which a solution containing an optical isomer noteasily adsorbed by the filler (raffinate) is taken out are assigned inthis order in the direction of fluid flow; and the working positions ofthese ports are intermittently and successively shifted in the directionof fluid flow.

In a simulated moving bed as shown in FIG. 1, an inlet port forintroducing the eluent; an outlet port for taking out the extract; aninlet port for introducing a solution containing a racemic compound; andan outlet port for taking out the raffinate are respectively assigned atevery third unit column. In order to intermittently and successivelyshift the role of the inlet ports and outlet ports, rotary valve,electromagnetic valve, air-actuated valve, etc. are used.

Separation by adsorption of a mevalonolactone compound in the simulatedmoving bed chromatographic process is basically effected by continuouslyand cyclically carrying out the adsorption step, the concentration step,the desorption step and the eluent recovery step.

(1) Adsorption Step

A mevalonolactone compound in the form of racemic mixture is madecontact with the optical resolution filler, whereby an optical isomerwhich is strongly adsorbed by the filler (the adsorbable) is adsorbed,and another optical isomer which is not easily adsorbed by the filler(the weakly adsorbable) is recovered together with the eluent.

(2) Concentration Step

The optical resolution filler which has adsorbed the adsorbable iscontacted with a portion of the extract described below and the weaklyadsorbable which is retained on the optical resolution filler isexpelled and thus the adsorbable is concentrated.

(3) Desorption Step

The optical resolution filler which has adsorbed the strongly adsorbableis contacted with the eluent, the adsorbable is expelled from the fillerand taken out of the simulating moving bed together with the eluent asextract.

(4) Eluent Recovery Step

The optical resolution filler which contains substantially the eluentonly is contacted with a portion of the raffinate and a portion of theeluent contained in the optical resolution filler is recovered as aneluent recovery.

The process is more specifically described with reference to theattached drawing.

In FIG. 1, unit columns 1-12 are filled with an optical resolutionfiller and they are mutually connected with fluid passages. The eluentis introduced through an eluent supply conduit 13: the extract is takenout through an extract conduit 14, the solution containing a racemiccompound is supplied via conduit 15, the raffinate is taken out througha raffinate conduit 16 and the fluid is recirculated through arecirculation conduit 17 by means of a pump 18.

In the state of the unit columns 1-12 and conduits 13-16 as indicated inFIG. 1, desorption is effected in unit columns 1-3, concentration iseffected in unit columns 4-6, adsorption is effected in unit columns 7-9and eluent recovery is effected in unit columns 10-12.

In the simulated moving bed like this, the working positions of theeluent supply conduit, the conduit which supplies a solution containinga racemic compound, respective extract conduits are shifted one unitcolumn by one unit column in the fluid flow direction at a constant timeinterval by operation of valves.

In the second stage, therefore, desorption is effected in unit columns2-4, concentration is effected in unit columns 5-7, adsorption iseffected in unit columns 8-10 and eluent recovery is effected in unitcolumns 11-1. By repeating this operation successively, each step iscarried out in a set of unit columns which is shifted one column by onecolumn. Thus optical resolution of a mevalonolactone is efficientlyachieved.

The extract taken out of the simulated moving bed in accordance withthis invention contains an optical isomer at so high purity as not lessthan 90%, specifically not less than 95% or 98% for instance, and theraffinate contains the other isomer with the same level of the opticalpurity.

The simulated moving bed to be used for the process of the presentinvention is not limited to the one shown in FIG. 1 but also the one asindicated in FIG. 2 can be used.

In the arrangement of unit columns 1-8 and conduits 13-16 as shown inFIG. 2, eluent recovery is effected in unit column 1, adsorption iseffected in unit columns 2-5, concentration is effected in unit columns6-7 and desorption is effected in unit column 8 in the first stage.

In this simulated moving bed, the supply conduits and the taking-outconduits are shifted unit column by unit column by valve operation at aconstant time interval in the direction of fluid flow. Thus in the nextstage, eluent recovery is effected in unit column 2, adsorption iseffected in unit columns 3-6, concentration is effected in unit columns7-8 and desorption is effected in unit column 1.

In FIG. 1, the extract is concentrated in a first falling filmevaporator 19, the concentrate is further concentrated in a secondfalling film evaporator 20, still further in a wiped film evaporator 21;the recovered solvent is stored temporarily in a recovery tank 22, theconcentrated solution containing a concentrated optical isomer is storedin a storage tank 23, the raffinate is racemized in a racemization tank24 and the solvent stored in the recovery tank 22 is concentrated in anevaporator 25.

Meanwhile, the raffinate contains the optical isomer which is anantipode of the isomer contained in the extract. The solvent isrecovered from the raffinate in the same manner as recovery of thesolvent from the extract.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the schematic presentation of an apparatus by which theprocess of the present invention is carried out.

FIG. 2 is the schematic presentation of another apparatus by which theprocess of the present invention is carried out.

EMBODIMENTS OF THE INVENTION

Now the invention is described by way of working examples. Needless tosay, the invention is not limited to these examples only but can beworked with suitable modification within the scope of the gist of theinvention.

Terms used in the working examples are defined as follows.

Capacity factor k'={(retention time of antipode)-(dead time)}/(deadtime)

Separation factor α=(volume ratio of strongly-adsorbed antipode)/(volumeratio of weakly-adsorbed antipode)

Resolution factor Rs=2×(distance between peaks of strongly-adsorbedantipode and weakly-adsorbed antipode)/(sum of bands of two peaks)

EXAMPLE 1

Using a column 0.46 cm in inner diameter and 25 cm in length filled withsilica gel supporting cellulose tris(p-chlorophenylcarbamate)("CHIRALCELOF" marketed by Daicel Chemical Industries, Ltd. ), the (3R,5S) body andthe (3S, 5R) body of ethyl 7-2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl!-3,5-dihydroxy-6-heptenoatewere optically separated. Conditions of liquid phase chromatography,retention time of the two isomers, capacity factor, separation factor,resolution factor and order of elution are indicated in Table 1.

EXAMPLE 2

Using a column 0.46 cm in inner diameter and 25 cm in length filled withsilica gel supporting cellulose tris(p-methylphenylbenzoate) ("CHIRALCELOJ" marketed by Daicel Chemical Industries, Ltd. ), the (3R,5S) body andthe (3S, 5R) body of ethyl 7-2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl!-3,5-dihydroxy-6-heptenoatewere optically separated. Conditions of liquid phase chromatography,retention time of the two isomers, capacity factor, separation factor,resolution factor and order of elusion are indicated in Table 1.

EXAMPLE 3

Using a column 0.46 cm in inner diameter and 25 cm in length filled withsilica gel supporting cellulose triphenylcarbamate ("CHIRALCEL OC"marketed by Daicel Chemical Industries, Ltd.), the (3R,5S) body and the(3S, 5R) body of ethyl 7-2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl!3,5-dihydroxy-6-heptenoatewere optically separated. Conditions of liquid phase chromatography,retention time of the two isomers, capacity factor, separation factor,resolution factor and order of elution are indicated in Table 1.

EXAMPLE 4

Using a column 0.46 cm in inner diameter and 25 cm in length filled withsilica gel supporting cellulose tris(3,5-dimethylphenylcarbamate)("CHIRALCEL OD" marketed by Daicel Chemical Industries, Ltd. ), the(3R,5S) body and the (3S, 5R) body of ethyl 7-2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl!-3,5-dihydroxy-6-heptenoatewere optically separated. Conditions of liquid phase chromatography,retention time of the two isomers, capacity factor, separation factor,resolution factor and order of elution are indicated in Table 1.

EXAMPLE 5

Using a column 0.46 cm in inner diameter and 25 cm in length filled withsilica gel supporting cellulose tris(p-methylphenylcarbamate)("CHIRALCELOG" marketed by Daicel Chemical Industries, Ltd.), the (3R,5S) body andthe (3S, 5R) body of ethyl 7-2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl!-3,5-dihydroxy-6-heptenoatewere optically separated. Conditions of liquid phase chromatography,retention time of the two isomers, capacity factor, separation factor,resolution factor and order of elution are indicated in Table 1.

EXAMPLE 6

Using a column 0.46 cm in inner diameter and 25 cm in length filled withsilica gel supporting amylose tris((s)-1-phenylethylcarbamate)("CHIRALPAK AS" marketed by Daicel Chemical Industries, Ltd.), racemicethyl 7-2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl!-5-hydroxy-3-oxo-6-heptenoatewas optically separated. Conditions of liquid phase chromatography,retention time of the two isomers,

                                      TABLE 1    __________________________________________________________________________            Example 1                    Example 2                            Example 3                                    Example 4                                            Example 5    __________________________________________________________________________    Filler  CHIRALCEL OF                    CHIRALCEL OJ                            CHIRALCEL OD                                    CHIRALCEL OD                                            CHIRALCEL OG    __________________________________________________________________________    Conditions    Eluent  H/I = 80/20                    H/E = 95/5                            H/E = 95/5                                    H/I = 95/5                                            H/E = 95/5    (vol. ratio)    Flow rate            1.0     1.0     1.0     1.0     1.0    (ml/min.)    Column temp.            40      22      22      22      22    (° C.)    __________________________________________________________________________    Detection            UV detector Wave length: 254 nm    __________________________________________________________________________    Parameters    Retention time            10.1    37.3    37.4    23.0    34.1    (ml/min.)            13.4    43.5    40.7    25.1    37.5    Capacity factor            2.37    11.42   11.47   6.65    10.37    (k.sub.1 ')    Separation factor            1.47    1.18    1.10    1.11    1.11    (a)    Resolution factor            3.63    1.56    0.89    1.17    1.26    (Rs)    Order of elution            (1) (3R, 5S)                    (1) (3S, 5R)                            (1) (3S, 5R)                                    (1) (3R, 5S)                                            (1) (3S, 5R)            (2) (3S, 5R)                    (2) (3R, 5S)                            (2) (3R, 5S)                                    (2) (3S, 5R)                                            (2) (3R, 5S)    __________________________________________________________________________

                  TABLE 2    ______________________________________                 Example 6   Example 7    ______________________________________    Filler       CHIRALCEL AS                             CHIRALCEL AD    ______________________________________    Conditions    Eluent       H/I = 90/10 H/I = 90/10    (vol. ratio)    Flow rate    1.0         1.0    (ml/min.)    Column temp. 5           40    (° C.)    ______________________________________    Detection    UV detector Wave length: 254 nm    ______________________________________    Parameters    Retention time                 22.5        8.2    (ml/min.)    37.7        8.9    Capacity factor                 6.51        1.74    (k.sub.1 ')    Separation factor                 1.78        1.12    (a)    Resolution factor                 1.56        0.51    (Rs)    ______________________________________

capacity factor, separation factor, resolution factor and order ofelution are indicated in Table 2.

EXAMPLE 7

Using a column 0.46 cm in inner diameter and 25 cm in length filled withsilica gel supporting amylose tris(3,5-dimethylphenylcarbamate)("CHIRALPAK AD" marketed by Daicel Chemical Industries, Ltd.), racemicethyl 7-2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl!-5-hydroxy-3-oxo-6-hepteno-atewere optically separated. Conditions of liquid phase chromatography,retention time of the two isomers, capacity factor, separation factor,resolution factor and order of elution are indicated in Table 2.

EXAMPLE 8

To a simulated moving bed chromatographic apparatus, which compriseseight (8) columns, each having an inner diameter of 1 cm and a length of25 cm filled with silica gel supporting cellulosetris(p-chlorophenylcarbamate) ("CHIRALCEL OF", particle diameter 20 μm,marketed by Daicel Chemical Industries, Ltd.) racemic ethyl 7-2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl!-3,5-dihydroxy-6-heptenoate((3R, 5S) isomer and (3S, 5R) isomer) was supplied at a rate of 1.0ml/min (racemic mixture concentration 3.5 mg/ml). The apparatus wasoperated under the following conditions:

Eluent: n-hexane/2-propanol (8/2 vol) mixture

Supply rate of eluent: 7 ml/min

Flow rate at outlet for solution rich in strongly adsorbable: 5.6 ml/min

Flow rate at outlet for solution rich in weakly adsorbable: 2.4 ml/min

Shift interval: 21.0 min

Temperature: room temp.

As a result, out of the outlet port for the fluid rich in the stronglyadsorbable, ethyl (-)-7-2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl!-3,5-dihydroxy-6-heptenoate((3S,5R) isomer) was obtained with a concentration of 530 ppm and anoptical purity of 65% ee. Out of the outlet port for the fluid rich inthe weakly adsorbable, ethyl (+)-7-2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl!-3,5-dihydroxy-6-heptenoate((3R,5S) isomer) was obtained with a concentration of 894 ppm and anoptical purity of 100% ee.

EXAMPLE 9

To a simulated moving bed chromatographic apparatus, which compriseseight (8) columns, each having an inner diameter of 1 cm and a length of25 cm filled with cellulose tris(p-chlorophenylcarbamate) ("CHIRALCELOF", particle diameter 20 μm, marketed by Daicel Chemical Industries,Ltd.), communicably connected in series, racemic ethyl 7-2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl!-3,5-dihydroxy-3,5-dihydroxy-6-heptenoate((3R, 5S) isomer and (3S, 5R) isomer) was supplied at a rate of 2.0ml/min (racemic mixture concentration 5.0 mg/ml). The apparatus wasoperated under the following conditions:

Eluent: n-hexane/2-propanol (8:2 vol) mixture

Supply rate of eluent: 7.2 ml/min

Flow rate at outlet for solution rich in strongly adsorbable: 7.2 ml/min

Flow rate at outlet for the solution rich in the weakly adsorbable: 4.8ml/min

Shift interval: 9.25 min

Temperature: 25° C.

As a result, out of the outlet port for the fluid rich in the stronglyadsorbable, ethyl (-)-7-2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl!-3,5-dihydroxy-6-heptenoate((3S,5R) isomer) was obtained with a concentration of 1233 ppm and anoptical purity of 45% ee. Out of the outlet for the fluid rich in theweakly adsorbable, ethyl (+)-7-2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl!-3,5-dihydroxy-6-heptenoate((3R,5S) isomer) was obtained with a concentration of 1146 ppm and anoptical purity of 99% ee.

Industrial Applicability

In accordance with the present invention, mevalonolactone compounds canbe efficiently separated and high optical purity mevalonolactonecompound can be prepared.

We claim:
 1. A process for preparing an optically active mevalonolactone compound comprising conducting optical resolution of the racemic form of an optically active mevalonolactone compound by means of batch system chromatography which uses a column filled with a filler selected from a group consisting of particles of a polysaccharide ester derivative, particles of a polysaccharide carbamate derivative and particles of a support which carries a polysaccharide ester derivative and/or a polysaccharide carbamate derivative.
 2. The process for preparing an optically active mevalonolactone compound as described in claim 1, wherein the polysaccharide ester derivative and the polysaccharide carbamate derivative are those in which part of or all of the hydrogen atoms on the hydroxy groups or amino groups of the polysaccharide are substituted with an atom groups represented by any of the following chemical formulas (1) to (4): ##STR9## wherein R stands for an aromatic group which may contain a hetero atom and may be unsubstituted or substituted with at least one selected from a group consisting of an alkyl group having 1-12 carbon atoms, an alkoxy group having 1-12 carbon atoms, an alkylthio group having 1-12 carbon atoms, a cyano group, a halogen atom, an acyl group having 1-8 carbon atoms, an acyloxy group having 1-8 carbon atoms, a hydroxy group, an alkoxycarbonyl group having 1-12 carbon atoms, a nitro group, an amino group and an alkylamino group having 1-8 carbon atoms; and X stands for a hydrocarbon group having 1-4 carbon atoms, which may contain a double bond or triple bond.
 3. A process for preparing an optically active mevalonolactone compound comprising forming a circulation flow circuit comprising a plurality of columns filled with an optical resolution filler and endlessly connected in series; enforcing a fluid to flow through the circuit in one direction; providing each with an inlet port through which the fluid is introduced into the column in the flow direction and with an outlet port, through which the fluid is taken out; intermittently shifting the working position of the inlet port and a suitably-spaced outlet port in the direction of the fluid flow; introducing a solution containing a racemic mevalonolactone compound and an eluent through an inlet port into the circuit; and simultaneously taking out a solution rich in the weakly adsorbable and a solution rich in the strongly adsorbable through the outlet port,wherein the optical resolution filler is one selected from a group consisting of particles of a polysaccharide ester derivative, particles of a polysaccharide carbamate derivative and particles of a support which carries a polysaccharide ester derivative and/or a polysaccharide carbamate derivative.
 4. The process for preparing an optically active mevalonolacton compounds as described in claim 3, wherein the polysaccharide ester derivative and the polysaccharide are those in which part of or all of the hydrogen atoms on the hydroxy groups or amino groups of the polysaccharide are substituted with any of the atom groups represented by the following chemical formulas (1) to (4): ##STR10## wherein R stands for an aromatic group which may contain a hetero atom and may be unsubstituted or substituted with at least one selected from a group consisting of an alkyl group having 1-12 carbon atoms, an alkoxy group having 1-12 carbon atoms, an alkylthio group having 1-12 carbon atoms, a cyano group, a halogen atom, an acyl group having 1-8 carbon atoms, an acyloxy group having 1-8 carbon atoms, a hydroxy group, an alkoxycarbonyl group having 1-12 carbon atoms, a nitro group, an amino group and an alkylamino group having 1-8 carbon atoms; and X stands for a hydrocarbon group having 1-4 carbon atoms, which may contain a double bond or triple bond.
 5. The process for preparing an optically active mevalonolactone compound as described in any of claims 1 to 4, wherein the optically active mevalonolacton compound is ethyl 7- 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl!-5-hydroxy3-oxo-6-heptenoate or ethyl 7- 2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl!-3,5-dihydroxy-6-heptenoate. 